Open AccessProtection of ischemic white matter and oligodendrocytes in mice by 3K3A-activated protein C
Author(s) -
Mikko T Huuskonen,
Yaoming Wang,
Angeliki M. Nikolakopoulou,
Axel Montagne,
Zhendong Dai,
Divna Lazić,
Abhay P. Sagare,
Zhen Zhao,
José A. Fernández,
John H. Griffin,
Berislav V. Zloković
Publication year - 2021
Publication title -
the journal of experimental medicine/the journal of experimental medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 8.483
H-Index - 448
eISSN - 1540-9538
pISSN - 0022-1007
DOI - 10.1084/jem.20211372
Subject(s) - neuroprotection , white matter , stroke (engine) , neuroscience , medicine , corpus callosum , microglia , dementia , neuroinflammation , vascular dementia , astrocyte , psychology , central nervous system , inflammation , magnetic resonance imaging , disease , engineering , radiology , mechanical engineering
Subcortical white matter (WM) stroke accounts for 25% of all strokes and is the second leading cause of dementia. Despite such clinical importance, we still do not have an effective treatment for ischemic WM stroke, and the mechanisms of WM postischemic neuroprotection remain elusive. 3K3A-activated protein C (APC) is a signaling-selective analogue of endogenous blood protease APC that is currently in development as a neuroprotectant for ischemic stroke patients. Here, we show that 3K3A-APC protects WM tracts and oligodendrocytes from ischemic injury in the corpus callosum in middle-aged mice by activating protease-activated receptor 1 (PAR1) and PAR3. We show that PAR1 and PAR3 were also required for 3K3A-APC’s suppression of post–WM stroke microglia and astrocyte responses and overall improvement in neuropathologic and functional outcomes. Our data provide new insights into the neuroprotective APC pathway in the WM and illustrate 3K3A-APC’s potential for treating WM stroke in humans, possibly including multiple WM strokes that result in vascular dementia.